rs1994798

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005957.5(MTHFR):c.1166+31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,613,318 control chromosomes in the GnomAD database, including 280,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24790 hom., cov: 32)

Exomes 𝑓: 0.59 ( 256165 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.42

Publications

36 publications found

Variant links:

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR Gene-Disease associations (from GenCC):

homocystinuria due to methylene tetrahydrofolate reductase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-11794698-G-A is Benign according to our data. Variant chr1-11794698-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.1166+31C>T		intron_variant	Intron 7 of 11	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.1166+31C>T		intron_variant	Intron 7 of 11	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85364

AN:

151888

Hom.:

24771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.436

Gnomad AMI

AF:

0.616

Gnomad AMR

AF:

0.688

Gnomad ASJ

AF:

0.617

Gnomad EAS

AF:

0.760

Gnomad SAS

AF:

0.484

Gnomad FIN

AF:

0.640

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.563

GnomAD2 exomes

AF:

0.607

AC:

152736

AN:

251438

AF XY:

0.599

show subpopulations

Gnomad AFR exome

AF:

0.433

Gnomad AMR exome

AF:

0.773

Gnomad ASJ exome

AF:

0.610

Gnomad EAS exome

AF:

0.760

Gnomad FIN exome

AF:

0.645

Gnomad NFE exome

AF:

0.588

Gnomad OTH exome

AF:

0.602

GnomAD4 exome

AF:

0.588

AC:

859672

AN:

1461312

Hom.:

256165

Cov.:

AF XY:

0.584

AC XY:

424900

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.435

AC:

14569

AN:

33468

American (AMR)

AF:

0.761

AC:

34017

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

16044

AN:

26130

East Asian (EAS)

AF:

0.774

AC:

30735

AN:

39700

South Asian (SAS)

AF:

0.469

AC:

40469

AN:

86242

European-Finnish (FIN)

AF:

0.650

AC:

34687

AN:

53390

Middle Eastern (MID)

AF:

0.473

AC:

2730

AN:

5768

European-Non Finnish (NFE)

AF:

0.586

AC:

651355

AN:

1111520

Other (OTH)

AF:

0.581

AC:

35066

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19772

39545

59317

79090

98862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17882

35764

53646

71528

89410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.562

AC:

85425

AN:

152006

Hom.:

24790

Cov.:

AF XY:

0.565

AC XY:

41967

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.436

AC:

18084

AN:

41452

American (AMR)

AF:

0.688

AC:

10519

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

2142

AN:

3470

East Asian (EAS)

AF:

0.759

AC:

3908

AN:

5146

South Asian (SAS)

AF:

0.483

AC:

2325

AN:

4810

European-Finnish (FIN)

AF:

0.640

AC:

6760

AN:

10556

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.586

AC:

39801

AN:

67972

Other (OTH)

AF:

0.562

AC:

1187

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1853

3706

5559

7412

9265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.588

Hom.:

8580

Bravo

AF:

0.564

Asia WGS

AF:

0.617

AC:

2147

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.023

(source)

DANN

Benign

0.69

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over